Mitochondrial Matrix Metalloproteinase-2 and Cardiac Injury Modulation of cardiac structure and function by matrix metalloproteinases (MMP) has become an area of intense interest. Much effort has been focused on the activity of a specific MMP, (MMP-2), in models of cardiac injury and in the settings of myocardial infarction or congestive heart failure. Clinically, MMP-2 directly contributes to progressive ventricular remodeling and congestive heart failure and a further understanding of the role(s) of this enzyme is critically important. In this Proposal we provide evidence for a previously unrecognized intracellular isoform of MMP-2 (mito-MMP-2) that specifically targets mitochondria. Mito-MMP-2 induces mitochondria-to-nuclear stress signaling, with activation of NF-:B and Nuclear Factor of Activated T-cell (NFAT) signaling cascades. Genes induced by these signaling cascades are critical components of the innate immune system and include pro-inflammatory chemokines and pro-apoptotic factors which lead to cardiomyocyte apoptosis and inflammatory cell infiltration. Transgenic mice expressing mito-MMP-2 exhibit progressive ventricular hypertrophy, severe contractile defects and enhanced injury following ex vivo ischemia/reperfusion injury. We propose to perform a quantitative analysis of the cardiac pathophysiology of the mito-MMP-2 transgenic mice and to determine the temporal pattern of activation of innate immunity genes which contribute to cardiomyocyte apoptosis and inflammation. Further, we will determine the mitochondrial proteolytic targets of mito-MMP-2 and assess the effects of this enzyme on cardiac mitochondrial bioenergetics and ventricular contractile function. These studies will hopefully provide new insights into the pathophysiology of progressive ventricular failure and possibly present new opportunities for therapeutic intervention for this common and severely disabling disorder.